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injury &
trauma
Dr. Hiwa Omer Ahmed
Assistant Professor in Surgery

The host response to injury—surgical,
traumatic, or infectious—is
characterized by various endocrine,
metabolic, and immunologic
alterations.
1. ENDOCRINE RESPONSE
TO INJURY

The classic response to injury comprises
multiple axes. These hormone response
pathways are activated by
► (1) mediators released by the injured
tissue,
► (2) neural and nociceptive input
originating from the site of injury, or
► (3) baroreceptor stimulation from
intravascular volume depletion.

. Thehormones released in
response to these activating
stimuli may be divided
into those primarily under
hypothalamopituitary control
and those primarily under
autonomic nervous system
control
Hormones Under Anterior
Pituitary Regulation


Pain, fear, anxiety, or emotional
arousal generate neural signals to the
paraventricular nucleus of the
hypothalamus, stimulating the
synthesis of
corticotropin-releasing hormone (CRH),
In the nonstressed healthy
► human
ACTH is synthesized, stored, and
released by the anterior pituitary
upon
CRH stimulation. ACTH is a 39–amino
acid peptide

being, ACTH release is regulated by
circadian signals; the greatest
elevation of ACTH occurs late at
night and
lasts until just before sunrise.
In trauma
► Mostinjury is characterized by
elevations in CRH and ACTH that are
proportional to the severity of injury
Cortisol/Glucocorticoids
► Cortisolis the major glucocorticoid in
human beings and is essential for
survival after significant physiological
stress.
In trauma

. Cortisol levels in response toinjury are not
under the influence of normal diurnal
variations and can remain persistently
elevated, depending on the type of systemic
stress.
Burn patients have demonstrated elevated
circulating cortisol levels for up to 4 weeks,
and soft-tissue injury and hemorrhage may
sustain elevated cortisol levels for up to a
week
Thyrotropin-Releasing
Hormone and Thyroid
Stimulating
► Hormone
Thyrotropin-releasing hormone (TRH)
serves as the primary stimulant for
the synthesis, storage, and release of
thyroid-stimulating hormone (TSH)
in the anterior pituitary. TSH in turn
stimulates thyroxine (T4) production
In trauma
► Although T3 levels are frequently decreased
after injury, there is no
compensatory rise in TSH release. After
major injury, reduced available T3
and circulating TSH levels are observed and
peripheral conversion of T4 to
T3 is impaired. concentrations remain
relatively constant.
► In severely injured orcritically ill patients, a
reduced free T4 concentration has been
predictive ofhigh mortality
Growth Hormones
► Hypothalamic growth hormone
releasing hormone (GHRH) travels
through
the hypothalamic-hypophyseal portal
circulation to the anterior pituitary and
stimulates the release of growth
hormone (GH) in a pulsatile fashion
mostly
during the sleeping hours.
In trauma
► There is a rise in circulating GH levels after
injury,The role of GH during stress is to
promote protein synthesis whileenhancing
the mobilization of fat stores. Fat
mobilization occurs by directstimulation in
conjunction with potentiation of adrenergic
lipolytic effects on
adipose stores. In the liver, hepatic
ketogenesis also is promoted by GH. GH
inhibits insulin release and decreases
glucose oxidation, leading to elevated
glucose levels
Somatostatin
► Somatostatin is a 14–amino acid
polypeptide produced by various cell
types, including gastric antrum cells
and pancreatic islet D cells
somatostatin
► The roleof somatostatin in the
response to injury is unclear, but it
may regulate
excessive nutrient absorption and the
activities of GH and IGF during
convalescence from injury
Gonadotrophins and Sex
Hormones
► Luteinizing-hormone releasing
hormone (LHRH) or gonadotropin-
releasing
hormone (GnRH) is released from the
hypothalamus and stimulates follicle-
stimulating hormone (FSH) and
luteinizing hormone (LH) release from
the
anterior pituitary.
In trauma
► The most relevant
clinical correlation is seen after injury,
stress, or severe illness, when LH and
FSH release is suppressed. The reduction in
LH and FSH consequently
reduces estrogen and androgen secretion.
► Estrogens inhibit cell-mediated immunity,
natural killer cell activity, andneutrophil
function, but are stimulatory for antibody-
mediated immunity
► . Androgens appear to be
predominantly immunosuppressive.
Prolactin

► The hypothalamus suppresses


prolactin secretion from the anterior
pituitary by the activities of
LHRH/GnRH and dopamine
In trauma

Elevated prolactin levels after injury
have been reported in adults, whereas
reduced levels are noted in children.
► Like growth hormone, prolactin has
immunostimulatory properties
Endogenous Opioids & in
trauma
► Elevated endogenous opioids are
measurable after major operations or
insults to the patient
► Endorphins also influence the immune
system by increasing natural
killer cell cytotoxicity and T cell
blastogenesis. Interleukin-1 activates
Hormones Under Posterior
Pituitary Regulation

► Arginine Vasopressin
► Vasopressin or arginine vasopressin
(AVP) (or antidiuretic hormone, ADH) is
synthesized in the anterior
hypothalamus and transported by
axoplasmic flow to the posterior
pituitary for storage.
In truma
► Elevated AVP secretion is another
characteristic of trauma,
hemorrhage, open-heart surgery, and other
major operations. This
elevated level typically persists for 1 week
after the insult.
► This effect
in the splanchnic circulation may cause the
trauma-induced
ischemia/reperfusion phenomenon that
precedes gut barrier impairment.
Oxytocin

► Oxytocin and AVP are the only known


hormones secreted by the posterior
pituitary
► butthe role of oxytocin in the
injury response is unknown
3. Hormones of the Autonomic
System
► Catecholamines
Catecholamines exert significant
influence in the physiologic response
to
stress and injury.
► Bothof the major catecholamines,
norepinephrine and epinephrine, are
increased in
plasma after injury, with average
elevations of three to four times above
baseline immediately after injury,
reaching their peak in 24 to 48 h
before
returning to baseline levels
Aldosterone

► Themineralocorticoid aldosterone is
synthesized, stored, and released in
the adrenal zona glomerulosa. Its
release may be induced by
angiotensin II,
hyperkalemia, and the pituitary
hormone known as aldosterone
stimulating
factor (ASF),.
In trauma
► but ACTH is the most potent stimulus for
aldosterone release in the injured patient
► The major function of aldosterone is to
maintain intravascular volume by
conserving sodium and eliminating
potassium and hydrogen ions.
. After injury, ACTH stimulates a brief
burst of aldosterone release. Angiotensin II
induces a protracted aldosterone release
that persists well after ACTH returns to
baseline.
Renin-Angiotensin
► Reninis synthesized and stored primarily
within the renal juxtaglomerular
apparatus near the afferent arteriole. The
juxtaglomerular apparatuscomprises the
juxtaglomerular neurogenic receptor, the
juxtaglomerularcell, and the macula densa.
Renin initially exists in an inactive form as
prorenin. The activation of renin and its
release is mediated by ACTH, AVP,glucagon,
prostaglandins, potassium, magnesium, and
calcium.
In trauma
► their secreation increased in injury
► The renin-angiotensin system
participates in the response to injury
by maintaining volume homeostasis
Insulin
► The netresult of impaired insulin
production and function after injury is
stress-induced hyperglycemia, which is in
keeping with the general catabolic state.
► . In the injured patient, a biphasic pattern
of insulin
release is observed. The first phase occurs
within a few hours after injuryand is
manifested as a relative suppression of
insulin release, reflecting the
influence of catecholamines and
sympathetic stimulation. The later phase
ischaracterized by a return to normal or
excessive insulin production but with
persistent hyperglycemia, demonstrating a
Glucagon
► The release of glucagon after
injury is initially decreased, but returns
to normal 12 h later. By 24 h,
glucagon levels are supranormal and
can persist for up to 3 days.

IMMUNE
RESPONSE TO
INJURY
► Even after the normalization of
macroendocrine hormone function
after the primary injury, the
persistence
of systemic inflammation, the
progression of organ dysfunction, and
even
late mortality indicate the presence of
other potent mediators influencing
the injury response.
► These mediators usually are small proteins
or lipids
that are synthesized and secreted by
immunocytes. These micromolecules,
collectively referred to as cytokines, are
indispensable in tissue healing and
in the immune response generated against
microbial invasions. Asmounting evidence
suggests, the activities of these cytokine
mediators are
integrally related to classic hormone
function and metabolic responses to injury
Cytokine-Mediated Response

Cytokines exert their influence by
binding to specific cell receptors and
activating intracellular signaling
pathways leading to modulation of
gene
transcription. By this mechanism,
cytokines influence immune cell
production, differentiation,
proliferation, and survival
Tumor Necrosis Factor-
alpha
► The release of TNF-a in response to
acute injury is rapid and short-
lived.Experiments simulating an acute
inflammatory response by means of
endotoxin challenge in human
subjects have demonstrated a
monophasitumor necrosis factor
(TNF) appearance curve, peaking at
approximately 90 min and followed by
a return to undetectable levels within
4 h . Even with a half-life of 15 to 18
min, the brief appearance of TNF
caninduce marked metabolic and
hemodynamic changes and activate
Interleukin-1
► TNF-a also induces the biosynthesis
and release of interleukin-1 (IL-1)
from macrophages and endothelial
cells.
In truma
► Among its effects, IL-1 induces the
classic inflammatory febrile response
to
injury by stimulating local
prostaglandin activity in the anterior
hypothalamus. Associated with the
hypothalamic activity is the induction
of
anorexia by an IL-1 effect on the
satiety center
Interleukin-2

► Although necessary as an
inflammatory mediator in promoting T
lymphocyte proliferation,
immunoglobulin production, and gut
barrier
integrity, IL-2 has not been readily
detectable in the circulation during
acute injury. Similar to IL-1, its short
half-life of less than 10 min adds to
the difficulty in detecting it after injury
►METABOLIC
RESPONSE TO
INJURY

The description of human biochemical
responses to injury and the
classification of such responses into an
ebb and flow phase by Cuthbertson
and others provides a useful model by
which the metabolic response to
injury may be characterized
Ebb & flow phase

Ebb & flow

Except with the most minor injury, the flow
phase is ushered in by
compensatory mechanisms resulting from
volume repletion and cessation
of initial injury conditions. The metabolic
response associated with the flow
phase serves to direct energy and protein
substrates so as to preserve
critical organ function and repair damaged
tissues.
Energy balance
► These changes can reflect the
degree of underlying injury
► Injury of any magnitude beyond the
most trivial is associated with an
increase in energy expenditure and
increases in oxygen consumption that
vary directly with the severity of injury
Fat metabolism

Free fatty acids are a principal source
of energy after injury. Lipolysis is
enhanced by the immediate elevations
in ACTH, cortisol, catecholamines,
glucagon, and growth hormone levels,
reduction in insulin level, and
increased sympathetic nervous system
activity
Carbohydrate Metabolism
► Systemic glucose intolerance is well
documented in injured patients. By
contrast, basal insulin levels are elevated by
several times during the early
flow phase, indicating a state of relative
insulin resistance.
► Increases in plasma glucose levels are
proportional to the severity of injury
and to some extent are correlated with
surviva
Protein and Amino Acid Metabolism

► The intake of protein for a healthy


young adult is approximately 80 to
120
g, or 13 to 20 g of nitrogen per day.
Daily fecal and urinary excretion of
nitrogen is 2 to 3 g and 13 to 20 g,
respectively. After injury, daily
nitrogen excretion in the urine
increases to 30 to 50 g as urea
nitrogen
► The magnitude of nitrogen loss also is
related to the age, sex, and physical
condition of the patient. Young healthy
males lose more protein in response
to an injury than do women or the
elderly, presumably because they
have a
higher lean body mass than the latter
two patient subsets.